Tranilast compositions and cocrystals

ABSTRACT

Mew tranilast complexes and new tranilast cocrystais are disclosed. These include all tranilast nicotinamide complex, a 1:1 tranilast nicotinamide cocrystal, a 1:1 tranilast saccharin complex, a 1:1 tranilast saccharin cocrystal, a 1:1 tranilast gentisic acid complex, a 1:1 tranilast gentisic acid cocrystal, a 1:1 tranilast salicylic acid complex, a 1:1 tranilast salicylic acid cocrystal, a 1:1 tranilast urea complex, a 1:1 tranilast urea cocrystal, a 1:1 tranilast 4-amtnoben2oic acid complex, a 1:1 tranilast 4-am!nobers2oic acid cocrystal, a 1:1 tranilast 2,4-di′hydroxybenzoic acid complex and a 1:1 tranilast 2,4-dihydroxybenzoic acid cocrystal. Also disclosed are pharmaceutical compositions containing a tranilast complex or cocrystal of the invention and a pharmaceutically acceptable carrier. Methods of treatment using the tranilast complexes and cocrystais as well as the pharmaceutical compositions are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Patent Application 61/618,639,filed Mar. 30, 2012; the disclosure of which is incorporated herein byreference.

FIELD OF THE INVENTION

The invention relates to new tranilast compositions and tranilastcocrystals. The invention also relates to therapeutic uses of the newtranilast compositions or cocrystals as well as pharmaceuticalcompositions containing them.

BACKGROUND

Tranilast, (2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoicacid), shown below, is a therapeutic agent that exhibits ananti-allergic effect. It has been shown to inhibit the release ofinflammatory mediators, such as histamine, from mast cells and basophils(P. Zampini. Int J Immunopharmacol. 1983; 5(5): 431-5). Tranilast hasbeen used as an anti-allergic treatment, for several years in Japan andSouth Korea, for conditions such as allergic conjunctivitis, bronchialasthma, allergic rhinitis and atopic dermatitis.

Tranilast is currently marketed in Japan and South Korea by KisseiPharmaceutical Co. Ltd under the Rizaben® brand name. As well asdisplaying an anti-allergic effect tranilast has been shown to possessanti-proliferative properties. Tranilast was found to inhibit theproliferation of fibroblasts and suppress collagen synthesis (M. Isaji.Biochem Pharmacol. 1987; 36: 469-474) and also to inhibit thetransformation of fibroblasts to myofibroblasts and their subsequentcontraction (M. Isaji. Life Sci. 1994; 55: 287-292). On the basis ofthese effects tranilast is now also indicated for the treatment ofkeloids and hypertrophic scars. Its anti-fibrotic action is believed tobe due to its ability to inhibit transforming growth factor beta (TGF-β)(H. Suzawa. Jpn J Pharmacol. 1992 October; 60(2): 91-96). TGF-β inducedfibroblast proliferation, differentiation and collagen synthesis areknown to be key factors in the progression of idiopathic pulmonaryfibrosis and tranilast has been shown in-vivo to have potential in thetreatment of this chronic lung disease (T. Jiang. Afr J Pharm Pharmaco.2011; 5(10): 1315-1320). Tranilast has also been shown in-vivo to behave potential beneficial effects in the treatment of airway remodellingassociated with chronic asthma (S. C. Kim. J Asthma 2009; 46(9):884-894.

It has been reported that tranilast also has activity as an angiogenesisinhibitor (M. Isaji. Br. J Pharmacol. 1997; 122(6): 1061-1066). Theresults of this study suggested that tranilast may be beneficial for thetreatment of angiogenic diseases such as diabetic retinopathy and agerelated macular degeneration. As well as showing inhibitory effects onmast cells and fibroblasts, tranilast has also demonstrated an abilityto diminish tumor necrosis factor-alpha (TNF-α) from culturedmacrophages (H. O. Pae. Biochem Biophys Res Commun. 371: 361-365) andT-cells (M. Platten. Science. 310: 850-855), and inhibitedNF-kB-dependent transcriptional activation in endothelial cells (M.Spieker. Mol Pharmacol. 62: 856-863). Recent studies have revealed thattranilast attenuates inflammation and inhibits bone destruction incollagen induced arthritis in mice suggesting the possible usefulness oftranilast in the treatment of inflammatory conditions such as arthritis(N. Shiota. Br. Pharmacol. 2010; 159 (3): 626-635).

As has recently been demonstrated, in-vitro and in-vivo, tranilast alsopossesses an anti-tumor action. Tranilast has been shown to inhibit theproliferation, apoptosis and migration of several cell lines includingbreast cancer (R. Chakrabarti. Anticancer Drugs. 2009 June; 20(5):334-45) and prostate cancer (S. Sato. Prostate. 2010 February; 70(3):229-38) cell lines. In a study of mammary carcinoma in mice tranilastwas found to produce a significant reduction in metastasis (R.Chakrabarti. Anticancer Drugs. 2009 June; 20(5): 334-45). In a pilotstudy in humans, tranilast was shown to have the potential to improvethe prognosis of patients with advanced castration-resistant prostatecancer (K. Izumi. Anticancer Research. 2010 July; 30: 73077-81).

It has been reported that tranilast has the ability to induce or enhanceneurogenesis and, therefore, could be used as an agent to treat neuronalconditions such as cerebral ischemia, glaucoma, multiple sclerosis,amyotrophic lateral sclerosis, Alzheimer's disease, neurodegenerativetrinucleotide repeat disorders, neurodegenerative lysosomal storagediseases, spinal cord injury and trauma, dementia, schizophrenia andperipheral neuropathy (A. Schneider. EP2030617).

Tranilast's beneficial properties have been reported to have utility inseveral ocular conditions. Tranilast is currently approved in Japan andKorea far the treatment of allergic conjunctivitis. WO2010137681 claimsthe use of tranilast as a prophylactic or therapeutic agent for thetreatment of retinal diseases. The anti-fibrotic properties of tranilasthave been reported to be of benefit in maintaining the filtering blobduring glaucoma surgery and this has been demonstrated in a pilot studyin humans (E. Chihara. J Glaucoma. 1999; 11(2): 127-133). There havealso been several reported cases of the beneficial use of tranilast inthe prevention of postoperative recurrence of pterygium (C. Fukui. Jap JOpthalmol. 1999; 12: 547-549). Tsuji recently reported that tranilastmay be beneficial not only in the prevention of pterygium recurrence,but also for the inhibition of symblepharon and granuloma formation (A.Tsuji. Tokai J Exp Clin Med. 2011; 36(4): 120-123). Collectively it hasbeen demonstrated that tranilast possesses anti-allergic, anti-fibrotic,anti-inflammatory, anti-tumor, neurogenesis enhancing end angiogenesisinhibitory properties and as such may be useful for the treatment ofdiseases associated with such properties.

Tranilast occurs as a yellow crystalline powder that is identified byCAS Registry Number: 53902-12-8. As is typical of cinnamic acidderivatives (G. M. J. Schmidt J Chem. Soc. 1964: 2000) tranilast isphotochemically unstable when in solution, transforming into cis-isomerand dimer forms on exposure to light (N. Hori. Cehm Pharm Bull. 1999;47: 1713-1716). Although pure crystalline tranilast is photochemicallystable in the solid state it is practically insoluble in water (14.5μg/ml) and acidic media (0.7 μg/ml in pH 1.2 buffer solution) (Societyof Japanese Pharmacopoeia. 2002). Although tranilast has shown activityin various indications, it is possible that the therapeutic potential ofthe drug is currently limited by its poor solubility and photostability.High energy amorphous forms are often used as a means of improving thesolubility of poorly soluble APIs, however, literature shows thatamorphous solid dispersions of tranilast are not completely photostablein the solid state and that they undergo photodegradation on storagewhen exposed to light (S. Onoue. Eur J Pharm Sci. 2010; 39: 256-262).US20110136835 describes a combination of tranilast and allopurinol andits use in the treatment of hyperuricemia associated with gout and hasone mention of a “co-crystal form”, but lacks any further description orcharacterization.

There is a need therefore to develop tranilast compositions that haveimproved solubility and/or photostability. A new tranilast compositionand/or cocrystal of the invention answers one or both of these needs. Anew tranilast composition and/or cocrystal of the invention may haveother beneficial properties such as increased solubility, improveddissolution, and/or increased bioavailability when compared to tranilastitself.

Although therapeutic efficacy is the primary concern for an activepharmaceutical ingredient (API), the chemical composition and solidstate form (i.e., the crystalline or amorphous form) of the API can becritical to its pharmacological properties, such as bioavailability, andto its development as a viable drug candidate. Compositions andcrystalline forms of some API's have been used to alter the API'sphysicochemical properties. Each composition or crystalline form canhave different solid state (physical and chemical) properties. Thedifferences in physical properties exhibited by a novel solid stateforms (such as, for example, a polymorph of the API or a cocrystalcontaining the API, discussed below) may affect pharmaceutical andpharmacological properties such as storage stability, compressibilityand density (important in formulation and product manufacturing), and/orsolubility and dissolution rates (important factors in determiningbioavailability). For example, the rate of dissolution of an activeingredient in a patient's stomach fluid may have therapeuticconsequences since it impacts the rate at which an orally administeredactive ingredient may reach the patient's bloodstream. Because thesepractical properties are influenced by the solid state properties, e.g.the crystalline form of the API, they can impact the selection of aparticular compound as an API, the ultimate pharmaceutical dosage form,the optimization of manufacturing processes, and absorption in the body.

Physical properties of an API also have a major influence on the abilityto deliver a drug by a desired method. For example, if a drug isdelivered by inhalation physical properties relating to the API as aparticle, such as morphology, density, surface energy, charge,hygroscopicity, stability, dispersive properties and/or agglomeration,can come into play. The solid state form of the API, and as describedbelow, cocrystals of the API, provide opportunities to address, engineerand/or improve upon one or more of such properties and thereby uponmethods of delivery.

Obtaining crystalline forms of an API, when possible, is also extremelyuseful in drug development. It permits better characterization of thedrug candidate's chemical and physical properties. Crystalline formsoften have better chemical and physical properties than the API in itsamorphous state. Moreover, finding the most adequate solid-state formfor further drug development can reduce the time and the cost of thatdevelopment.

It may be possible to achieve more desirable properties of a particularAPI by forming a cocrystal of the API. A cocrystal of an API is adistinct chemical composition of the API and coformer(s) and generallypossesses distinct crystallographic and spectroscopic properties whencompared to those of the API and coformer(s) individually.Crystallographic and spectroscopic properties of crystalline forms aretypically measured by X-ray powder diffraction (XRPD) and single crystalX-ray crystallography, among other techniques. Cocrystals often alsoexhibit distinct thermal behavior. Thermal behavior is measured in thelaboratory by such techniques as capillary melting point,thermogravimetric analysis (TGA) and differential scanning calorimetry(DSC). As crystalline forms, cocrystals may possess more favorable solidstate, physical, chemical, pharmaceutical and/or pharmacologicalproperties or be easier to process than known forms or formulations ofthe API. For example, a cocrystal may have different dissolution and/orsolubility properties than the API and can therefore be more effectivein therapeutic delivery. New pharmaceutical compositions comprising acocrystal of a given API may therefore have different or superiorproperties as compared to its existing drug formulations.

SUMMARY OF THE INVENTION

The invention relates to new tranilast complexes and new tranilastcocrystals. In particular, the invention relates to a 1:1 tranilastnicotinamide complex, a 1:1 tranilast nicotinamide cocrystal, a 1:1tranilast saccharin complex, a 1:1 tranilast saccharin cocrystal, a 1:1tranilast gentisic acid complex, a 1:1 tranilast gentisic acidcocrystal, a 1:1 tranilast salicylic acid complex, a 1:1 tranilastsalicylic acid cocrystal, a 1:1 tranilast urea complex, a 1:1 tranilasturea cocrystal, a 1:1 tranilast 4-aminobenzoic acid complex, a 1:1tranilast 4-aminobenzoic acid cocrystal, a 1:1 tranilast2,4-dihydroxybenzoic acid complex and a 1:1 tranilast2,4-dihydroxybenzoic acid cocrystal. The invention relates topharmaceutical compositions containing a tranilast complex or cocrystalof the invention and a pharmaceutically acceptable carrier. Thetranilast complexes and cocrystals may be used in the same way astranilast. Tranilast possesses anti-allergic, anti-fibrotic,anti-inflammatory, anti-tumor, neurogenesis enhancing and angiogenesisinhibitory properties and as such may be useful for the treatment of thediseases, disorders and conditions associated with such properties, asdiscussed above.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows an XRPD diagram of the 1:1 tranilast nicotinamidecocrystal.

FIG. 2 shows an ORTEP drawing of the 1:1 tranilast nicotinamidecocrystal at 100 K.

FIG. 3 shows a calculated XRPD pattern for the 1:1 tranilastnicotinamide cocrystal at 100 K.

FIG. 4 shows a DSC trace for the 1:1 tranilast nicotinamide cocrystal.

FIG. 5 shows a TGA trace for the 1:1 tranilast nicotinamide cocrystal.

FIG. 6 shows the ¹H NMR spectrum of 1:1 tranilast nicotinamidecocrystal.

FIG. 7 shows an overlay of the XRPD patterns of the 1:1 tranilastnicotinamide cocrystal at various time points during a 6 monthaccelerated stability study at 40° C./75% RH.

FIG. 8 shows an XRPD diagram of the 1:1 tranilast saccharin cocrystal.

FIG. 9 shows a DSC trace for the 1:1 tranilast saccharin cocrystal.

FIG. 10 shows a TGA trace for the 1:1 tranilast saccharin cocrystal.

FIG. 11 shows the NMR spectrum of 1:1 tranilast saccharin cocrystal.

FIG. 12 shows an XRPD diagram of the 1:1 tranilast gentisic acidcocrystal.

FIG. 13 shows a DSC trace for the 1:1 tranilast gentisic acid cocrystal.

FIG. 14 shows a TGA trace for the 1:1 tranilast gentisic acid cocrystal.

FIG. 15 shows the ¹H NMR spectrum of 1:1 tranilast gentisic acidcocrystal.

FIG. 16 shows an XRPD diagram of the 1:1 tranilast salicylic acidcocrystal.

FIG. 17 shows a DSC trace for the 1:1 tranilast salicylic acidcocrystal.

FIG. 18 shows a TGA trace for the 1:1 tranilast salicylic acidcocrystal.

FIG. 19 shows the ¹H NMR spectrum of 1:1 tranilast salicylic acidcocrystal.

FIG. 20 shows an XRPD diagram of the 1:1 tranilast urea cocrystal.

FIG. 21 shows a DSC trace for the 1:1 tranilast urea cocrystal.

FIG. 22 shows a TGA trace for the 1:1 tranilast urea cocrystal.

FIG. 23 shows the ¹H NMR spectrum of 1:1 tranilast urea cocrystal.

FIG. 24 shows an XRPD diagram of the 1:1 tranilast 4-aminobenzoic acidcocrystal.

FIG. 25 shows a DSC trace for the 1:1 tranilast 4-aminobenzoic acidcocrystal.

FIG. 26 shows a TGA trace for the 1:1 tranilast 4-aminobenzoic acidcocrystal.

FIG. 27 shows the ¹H NMR spectrum of 1:1 tranilast 4-aminobenzoic acidcocrystal.

FIG. 28 shows an XRPD diagram of the 1:1 tranilast 2,4-dihydroxybenzoicacid cocrystal.

FIG. 29 shows a DSC trace for the 1:1 tranilast 2,4-dihydroxybenzoicacid cocrystal.

FIG. 30 shows a TGA trace for the 1:1 tranilast 2,4-dihydroxybenzoicacid cocrystal.

FIG. 31 shows the ¹H NMR spectrum of 1:1 tranilast 2,4-dihydroxybenzoicacid cocrystal.

FIG. 32 shows the dissolution profiles, over 30 minutes, for crystallinetranilast and the tranilast cocrystals of the invention, in purifiedwater containing 2% SDS.

DETAILED DESCRIPTION

The invention relates to new tranilast complexes and new tranilastcocrystals. In particular, the invention relates to a 1:1 tranilastnicotinamide complex, a 1:1 tranilast nicotinamide cocrystal, a 1:1tranilast saccharin complex, a 1:1 tranilast saccharin cocrystal, a 1:1tranilast gentisic acid complex, a 1:1 tranilast gentisic acidcocrystal, a 1:1 tranilast salicylic acid complex, a 1:1 tranilastsalicylic acid cocrystal, a 1:1 tranilast urea complex, a 1:1 tranilasturea cocrystal, a 1:1 tranilast aminobenzoic acid complex, a 1:1tranilast 4-aminobenzoic acid cocrystal, a 1:1 tranilast2,4-dihydroxybenzoic acid complex and a 1:1 tranilast2,4-dihydroxybenzoic acid cocrystal. The invention relates topharmaceutical compositions containing a tranilast complex or cocrystalof the invention and a pharmaceutically acceptable carrier. Thetranilast complexes and cocrystals and methods used to characterize themare described below.

Therapeutic Uses of Tranilast Complexes and Cocrystals

The invention further relates to the therapeutic use of the tranilastcomplexes and cocrystals of the invention, 1:1 tranilast nicotinamidecomplex, a 1:1 tranilast nicotinamide cocrystal, a 1:1 tranilastsaccharin complex, a 1:1 tranilast saccharin cocrystal, a 1:1 tranilastgentisic acid complex, a 1:1 tranilast gentisic acid cocrystal, a 1:1tranilast salicylic acid complex, a 1:1 tranilast salicylic acidcocrystal, a 1:1 tranilast urea complex, a 1:1 tranilast urea cocrystal,a 1:1 tranilast 4-aminobenzoic acid complex, a 1:1 tranilast4-aminobenzoic acid cocrystal, a 1:1 tranilast 2,4-dihydroxybenzoic acidcomplex and a 1:1 tranilast 2,4-dihydroxybenzoic acid cocrystal.Tranilast, as discussed above, is known to possess anti-allergic,anti-fibrotic, anti-inflammatory, anti-tumor, neurogenesis enhancing andangiogenesis inhibitory properties. The tranilast complexes andcocrystals of the invention may then be used, in the same way astranilast, to treat diseases, disorders and conditions, such as thosediscussed above, that are associated with such properties. Accordingly,the invention relates to the method of treating such a disease,disorder, or condition comprising the step of administering to a patientin need thereof a therapeutically effective amount of a tranilastcomplex or cocrystal of the invention or of administering to a patientin need thereof a therapeutic composition containing a tranilast complexor cocrystal of the invention.

The term “treatment” or “treating” means any treatment of a disease,disorder or condition in a mammal, including: preventing or protectingagainst the disease, disorder or condition, that is, causing theclinical symptoms not to develop; inhibiting the disease, disorder orcondition, that is, arresting or suppressing the development of clinicalsymptoms; and/or relieving the disease, disorder or condition (includingthe relief of discomfort associated with the condition or disorder),that is, causing the regression of clinical symptoms. It will beunderstood by those skilled in the art that in human medicine, it is notalways possible to distinguish between “preventing” and “suppressing”since the ultimate inductive event or events may be unknown, latent, orthe patient is not ascertained until well after the occurrence of theevent or events. Therefore, as used herein the term “prophylaxis” isintended as an element of “treatment” to encompass both “preventing” and“suppressing” the disease, disorder or condition. The term “protection”is meant to include “prophylaxis.”

Pharmaceutical Compositions Containing the Tranilast Complexes andCocrystals

The invention also relates to pharmaceutical compositions comprising atherapeutically effective amount of a tranilast complex or cocrystalaccording to the invention and a pharmaceutically acceptable carrier(also known as a pharmaceutically acceptable excipient). As mentionedabove, these pharmaceutical compositions are therapeutically useful totreat or prevent disorders such as those discussed above.

A pharmaceutical composition of the invention may be in anypharmaceutical form which contains a tranilast complex or cocrystalaccording to the invention. The pharmaceutical composition may be, forexample, a tablet, a capsule, a liquid suspension, an injectablecomposition, a topical composition, an inhalable composition or atransdermal composition. Liquid pharmaceutical compositions may beprepared comprising a tranilast complex of the invention. Thepharmaceutical compositions generally contain, for example, about 0.1%to about 99.9% by weight of a tranilast complex or cocrystal of theinvention, for example, about 0.5% to about 99% by weight of a tranilastcomplex or cocrystal of the invention and, for example, 99.5% to 0.5% byweight of at least one suitable pharmaceutical excipient. In oneembodiment, the composition may be between about 5% and about 75% byweight of a tranilast complex or cocrystal of the invention with therest being at least one suitable pharmaceutical excipient or at leastone other adjuvant, as discussed below.

A “therapeutically effective amount of a tranilast complex or cocrystalaccording to the invention” is that which correlates to the therapeuticeffect currently achieved when administering orally about 50-about 600mg of tranilast itself. As discussed above, tranilast is marketed inJapan and South Korea by Kissei Pharmaceutical Co. Ltd under theRizaben® brand name. Tranilast is prescribed orally to treat bronchialasthma, allergic rhinitis, atopic dermatitis, keloid or hypertrophicscar. The typical dosage in adults is currently one 100 mg tablet threetimes per day. Up until now tranilast has been used orally in very highquantities. This is because the oral bioavailability of the drug islikely to be extremely low. Firstly, as discussed above, tranilast is soinsoluble that only a tiny amount is absorbed in the gastrointestinalsystem. But secondly a large proportion of the absorbed drug is thenremoved by first pass metabolism. The absolute bioavailability in humansis not known, but a pharmacokinetic study in rats showed that therelative bioavailability of crystalline tranilast administered orallycompared to IV administration was only 1.2% (S. Onoue. Drug MetabPharmacokinet. 2012). A tranilast complex or cocrystal of the inventionhaving improved solubility and also delivered systemically by a meansthat avoids first pass metabolism (sublingual, buccal, IV, topical,inhaled, ophthalmic) can achieve the same efficacy as is currently knownfor tranilast with a significantly lower dose, even as low as about 1-2mg. Thus, a therapeutically effective amount of a tranilast complex orcocrystal of the invention may be in the range mentioned above but mayalso range from about 0.5 mg to about 250 mg, and even from about 1 mgto about 100 mg of the tranilast complex or cocrystal itself. Thetherapeutically effective amount of a drug can also depend upon theroute of administration as is known in the art. For example, in atopical application such as with a cream, eye drops, or in pulmonarydelivery the therapeutically effective amount may be small.

The actual amount required for treatment of any particular disease,disorder or condition for any particular patient may depend upon avariety of factors including, for example, the particular disease,disorder or condition being treated; the disease state being treated andits severity; the specific pharmaceutical composition employed; the age,body weight, general health, sex and diet of the patient; the mode ofadministration; the time of administration; the route of administration;and the rate of excretion of tranilast; the duration of the treatment;any drugs used in combination or coincidental with the specific compoundemployed; and other such factors well known in the medical arts. Thesefactors are discussed in Goodman and Gilman's “The Pharmacological Basisof Therapeutics”, Tenth Edition, A. Gilman, J. Hardman and L. Limbird,eds., McGraw-Hill Press, 155-173, 2001, which is incorporated herein byreference.

Depending on the type of pharmaceutical composition, thepharmaceutically acceptable carrier may be chosen from any one or acombination of carriers known in the art. The choice of pharmaceuticallyacceptable carrier depends upon the pharmaceutical form and the desiredmethod of administration to be used. For a solid pharmaceuticalcomposition of the invention, that is one containing a tranilastcocrystal of the invention, a carrier should be chosen that maintainsthe crystalline form. In other words, the carrier in a solidpharmaceutical composition should not substantially alter the tranilastcocrystal. Nor should the carrier be otherwise incompatible with thetranilast cocrystal used, such as by producing any undesirablebiological effect or otherwise interacting in a deleterious manner withany other component(s) of the pharmaceutical composition.

The pharmaceutical compositions of the invention may be prepared bymethods known in the pharmaceutical formulation art, for example, seeRemington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company,Easton, Pa., 1990), which is incorporated herein by reference. In asolid dosage form, a tranilast complex or cocrystal of the invention maybe admixed with at least one pharmaceutically acceptable excipient suchas, for example, sodium citrate or dicalcium phosphate or (a) fillers orextenders, such as, for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid, (b) binders, such as, for example, cellulosederivatives, starch, aliginates, gelatin, polyvinylpyrrolidone, sucrose,and gum acacia, (c) humectants, such as, for example, glycerol, (d)disintegrating agents, such as, for example, agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, croscarmellosesodium, complex silicates, and sodium carbonate, (e) solution retarders,such as, for example, paraffin, (f) absorption accelerators, such as,for example, quaternary ammonium compounds, (g) wetting agents, such as,for example, cetyl alcohol, and glycerol monostearate, magnesiumstearate and the like (h) adsorbents, such as, for example, kaolin andbentonite, and (i) lubricants, such as, for example, talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, or mixtures thereof. In the case of capsules, tablets, andpills, the dosage forms may also comprise buffering agents.

Pharmaceutically acceptable adjuvants known in the pharmaceuticalformulation art may also be used in the pharmaceutical compositions ofthe invention. These include, but are not limited to, preserving,wetting, suspending, sweetening, flavoring, perfuming, emulsifying, anddispensing agents. Prevention of the action of microorganisms may beensured by inclusion of various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, and the like. Itmay also be desirable to include isotonic agents, for example, sugars,sodium chloride, and the like. If desired, a pharmaceutical compositionof the invention may also contain minor amounts of auxiliary substancessuch as wetting or emulsifying agents, pH buffering agents,antioxidants, and the like, such as, for example, citric acid, sorbitanmonolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.

Solid dosage forms as described above may be prepared with coatings andshells, such as enteric coatings and others, as is known in thepharmaceutical art. They may contain pacifying agents, and can also beof such composition that they release the active compound or compoundsin a certain part of the intestinal tract in a delayed manner.Non-limiting examples of embedded compositions that may be used arepolymeric substances and waxes. The active compounds may also be inmicroencapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Suspensions, in addition to the active compounds, may contain suspendingagents, such as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,or mixtures of these substances, and the like. Liquid dosage forms maybe aqueous, may contain a pharmaceutically acceptable solvent as well astraditional liquid dosage form excipients known in the art whichinclude, but are not limited to, buffering agents, flavorants,sweetening agents, preservatives, and stabilizing agents.

Compositions for rectal administrations are, for example, suppositoriesthat may be prepared by mixing a tranilast complex or cocrystal of theinvention with, for example, suitable non-irritating excipients orcarriers such as cocoa butter, polyethyleneglycol or a suppository wax,which may be solid at ordinary temperatures but may be liquid at bodytemperature and, therefore, melt while in a suitable body cavity andrelease the active component therein.

Compositions suitable for topical administration include liquid orsemi-liquid preparations such as liniments, lotions, gels, applicants,oil-in-water or water-in-oil emulsions such as creams, ointments, pastesor foams; or solutions or suspensions such as drops, as is known in theart. Compositions of the invention may be intended for topicaladministration, in which case the carrier may suitably comprise asolution, emulsion, ointment or gel base. The carrier or base, forexample, may comprise one or more of the following: petrolatum, lanolin,polyethylene glycols, bee wax, mineral oil, diluents such as water andalcohol, and emulsifiers and stabilizers. Thickening agents may bepresent in a pharmaceutical composition for topical administration. Ifintended for transdermal administration, the composition may include atransdermal patch or iontophoresis device. Topical formulations maycontain a concentration of the compound of the invention from about 0.1to about 10% w/v (weight per unit volume).

In addition to the topical method of administration described above,there are various methods of administering the active tranilastcomplexes and cocrystals of the invention topically to the lung. Onesuch means could involve a dry powder inhaler formulation of respirableparticles comprised of the tranilast complexes or cocrystals of theinvention, which the patient being treated inhales. It is common for adry powder formulation to include carrier particles, to which thetranilast complex or cocrystal particles can adhere to. The carrierparticles may be of any acceptable pharmacologically inert material orcombination of materials. For example, the carrier particles may becomposed of one or more materials selected from sugar alcohols; polyols,for example sorbitol, mannitol or xylitol, and crystalline sugars,including monosaccharides and disaccharides; inorganic salts such assodium chloride and calcium carbonate; organic salts such as sodiumlactate; and other organic compounds such as urea, polysaccharides, forexample cyclodextrins and dextrins. The carrier particles may be acrystalline sugar, for example, a monosaccharide such as glucose orarabinose, or a disaccharide such as maltose, saccharose, dextrose orlactose. The tranilast complex or cocrystal would be dispersed into therespiratory tract, and subsequently contact the lower lung in apharmaceutically effective amount.

Another means of administering the active compounds topically to theeyes of the subject would involve administering a topical liquid/liquidsuspension in the form of eye drops or eye wash. Liquid pharmaceuticalcompositions of the active compound for producing an eye drop or eyewash formulation can be prepared by combining the active compound with asuitable vehicle, such as sterile pyrogen free water or sterile salineby techniques known to those skilled in the art.

In addition to the topical method of administration described above,there are various methods of administering the active tranilastcomplexes and cocrystals of the invention systemically by such methods.One such means would involve an aerosol suspension of respirableparticles comprised of the tranilast complexes or cocrystals of theinvention, which the patient being treated inhales. The tranilastcomplex or cocrystal would be absorbed into the bloodstream via thelungs in a pharmaceutically effective amount. The respirable particlescan be liquid or solid, with a particle size sufficiently small to passthrough the mouth and larynx upon inhalation.

Because the crystalline form of a tranilast cocrystal may be maintainedduring preparation, solid dosage forms are preferred for thepharmaceutical composition of the invention. Dosage forms for oraladministration, which includes capsules, tablets, pills, powders,granules, and suspensions may be used. Dosage forms for pulmonaryadministration, which includes metered dose inhaler, dry powder inhaleror aerosol formulations may be used. In such solid dosage forms, theactive compound may be mixed with at least one inert, pharmaceuticallyacceptable excipient (also known as a pharmaceutically acceptablecarrier). A tranilast complex and cocrystal according to the inventionmay also be used to formulate liquid or injectable pharmaceuticalcompositions. Administration of a tranilast complex or cocrystal in pureform or in an appropriate pharmaceutical composition may be carried outvia any of the accepted modes of administration or agents for servingsimilar utilities. Thus, administration may be, for example, orally,buccally, nasally, pulmonary, parenterally (intravenous, intramuscular,or subcutaneous), topically, transdermally, intravaginally,intravesically, intrasystemically, ophthalmically or rectally, in theform of solid, semi-solid, lyophilized powder, or liquid dosage forms,such as, for example, tablets, suppositories, pills, soft elastic andhard gelatin capsules, powders, solutions, suspensions, or aerosols, orthe like, such as, for example, in unit dosage forms suitable for simpleadministration of precise dosages. One route of administration may beoral administration, using a convenient daily dosage regimen that can beadjusted according to the degree of severity of the condition to betreated.

EXAMPLES

The following analytical methods were used to characterize the tranilastcomplexes and cocrystals of the invention. For work done at roomtemperature (RT) that is generally about 25° C.

X-Ray Powder Diffraction Characterisation:

X-ray powder diffraction patterns for the samples were acquired on aBruker D8 diffractometer using CuKα radiation (40 kV, 40 mA), θ-2θgoniometer, V4 receiving slits, a Ge monochromator and a Lynxeyedetector. The instrument is performance checked using a certifiedCorundum standard (NIST 1976). The data were collected over an angularrange of 2° to 42° 2Θ using a step size of 0.05° 2Θ and a step time of0.5 seconds. Samples run under ambient conditions were prepared as flatplate specimens using powder as received without grinding.Approximately, 35 mg of the sample was gently packed into a cavity cutinto polished, zero background (510) silicon wafer. All samples wereanalyzed using Diffrac Plus EVA v11.0.0.2 or v13.0.0.2.

Single Crystal X-Ray Diffraction (SCXRD):

Data were collected on an Oxford Diffraction SuperNova Dual source, Cuat zero, Atlas CCD Diffractometer equipped with an Oxford CryosystemsCryostream cooling device. Structures were solved using the BrukerSHELXTL program and refined with the SHELXTL program as part of theBruker SHELXTL suite. Unless otherwise stated, hydrogen atoms attachedto carbon were placed geometrically and allowed to refine with a ridingisotropic displacement parameter. Hydrogen atoms attached to aheteroatom were located in a difference Fourier synthesis and wereallowed to refine freely with an isotropic displacement parameter.

Thermal Analysis—Differential Scanning Calorimetry (DSC):

DSC data were collected on a PerkinElmer Pyris 4000 DSC equipped with a45 position sample holder. The instrument was verified for energy andtemperature calibration using certified indium. A predefined amount ofthe sample, 0.5-3.0 mg, was placed in a pin holed aluminium pan andheated at 20° C.·min⁻¹ from 30 to 350° C. A purge of dry nitrogen at 60ml·min⁻¹ was maintained over the sample. The instrument control, dataacquisition and analysis were performed with Pyris Software v9.0.1.0203.

Thermo-Gravimetric Analysis (TGA):

TGA data were collected on a PerkinElmer Pyris 1 TGA equipped with a 20position auto-sampler. The instrument was calibrated using a certifiedweight and certified Alumel and Perkalloy for temperature. A predefinedamount of the sample, 1-5 mg, was loaded onto a pre-tared aluminiumcrucible and was heated at 20° C.·min⁻¹ from ambient temperature to 400°C. A nitrogen purge at 20 ml·min⁻¹ was maintained over the sample. Theinstrument control, data acquisition and analysis were performed withPyris Software v9.0.1.0203.

Solution Proton NMR:

¹H-NMR spectra were collected using a JEOL EX 270 MHz spectrometerequipped with an auto-sampler. The samples were dissolved in d6-DMSO foranalysis. The data was acquired using Delta NMR Processing and ControlSoftware version 4.3.

Stability Study X-Ray Powder Diffraction Characterisation:

X-Ray Powder Diffraction patterns at the required time points werecollected on a PANalytical diffractometer using Cu Kα radiation (45 kV,40 mA), θ-θ goniometer, focusing mirror, divergence slit (½″), sollerslits at both incident and divergent beam (4 mm) and a PIXcel detector.The software used for data collection was X'Pert Data Collector, version2.2f and the data was presented using X'Pert Data Viewer, version 1.2d.Instrument verification was performed using a silicon and benzoic acidstandard, performed with the same batch program as listed below forsample analysis. Samples were run under ambient conditions and wereanalyzed by transmission foil XRPD, using the powder as received.Approximately 2-5 mg of the sample was mounted on a 96 position sampleplate supported on a polyimide (Kapton, 12.7 μm thickness) film. Plateheight (Z) was set to 9 mm. Data was collected in the range 3-40° 2θwith a continuous scan (speed of 0.2° 2θ/s).

Example 1 1:1 Tranilast Nicotinamide Cocrystal

1.1 Preparation of a 1:1 Tranilast Nicotinamide Cocrystal

The batch of the 1:1 tranilast nicotinamide cocrystal used forcharacterisation was prepared as follows:

Tranilast (100 mg) and nicotinamide (37.3 mg) were weighed into a glassvial. Isopropyl acetate (1.5 ml) was added to the vial. The resultingyellow slurry was placed in a shaker and matured for 5 days (roomtemperature (RT, ^(˜)25° C.) to 50° C. on an 8 hour cycle, heating to50° C. for 4 hours and then cooling to RT for a further 4 hours). Theproduct was then filtered under vacuum and the resulting colourlesscrystals were dried under ambient conditions overnight.

1.2 XRPD Characterisation of a 1:1 Tranilast Nicotinamide Cocrystal

The experimental XRPD pattern of the 1:1 tranilast nicotinamidecocrystal is shown in FIG. 1. Table 1 lists the angles, °2θ±0.2°2θ, andd-spacing of the peaks identified in the experimental XRPD pattern ofFIG. 1. The entire list of peaks, or a subset thereof, may be sufficientto characterize the cocrystal, as well as by an XRPD patternsubstantially similar to FIG. 1. For example, a 1:1 tranilastnicotinamide cocrystal of the invention may be characterised by a powderX-ray diffraction pattern having at least three peaks selected from 6.0,8.0, 12.0, 15.0 and 15.6 °2θ±0.2°2θ.

TABLE 1 Angle d value °2θ ± 0.2 °2θ Angstrom Intensity % 6.0 14.63 20.38.0 11.02 21.5 9.0 9.85 29.6 9.2 9.60 43.6 12.0 7.35 3.7 12.9 6.87 13.714.0 6.31 21.9 15.0 5.89 100.0 15.6 5.66 16.5 16.1 5.50 6.1 16.7 5.294.0 18.0 4.94 71.6 18.4 4.81 37.4 19.4 4.56 10.2 19.7 4.51 14.5 20.74.29 17.1 21.1 4.21 18.4 21.6 4.10 10.5 22.2 4.00 9.9 22.9 3.87 31.223.3 3.82 29.2 24.2 3.67 10.4 25.0 3.56 20.6 25.2 3.53 11.6 26.2 3.3915.9 27.3 3.26 9.8 28.4 3.14 30.5 28.7 3.11 22.1 30.3 2.95 6.4 32.5 2.759.3 33.8 2.65 6.7 34.6 2.59 4.7 36.5 2.46 4.5 37.0 2.43 5.5 37.8 2.388.1

1.3 SCXRD Characterisation of a 1:1 Tranilast Nicotinamide Cocrystal

The crystal used for single crystal structure determination was preparedas follow: Approximately 20 mg (estimated by eye) of the 1:1 tranilastnicotinamide cocrystal batch prepared as previously described was placedin a glass HPLC vial and 1 ml of dichloromethane was added. The samplewas placed on a shaker at 50° C. for ca. 30 minutes before being removedand quickly filtered into a clean glass vial. The vial was covered withfilm which was then pierced to allow slow evaporation and crystalformation. A suitable single crystal was isolated from the crystals thatwere formed by this method.

The single crystal data and structure refinement parameters for thestructure measured at 100 K are reported in Table 2, below. An ORTEPdiagram of the 1:1 tranilast nicotinamide cocrystal at 100 K showing thenumbering system employed is shown in FIG. 2. Anisotropic atomicdisplacement ellipsoids for the non-hydrogen atoms are shown at the 50%probability level and hydrogen atoms are displayed as spheres ofarbitrary radius. The calculated XRPD pattern based on the singlecrystal data and structure for the 1:1 tranilast nicotinamide cocrystalat 100 K is shown in FIG. 3. It is also noted that there are some smalltemperature shifts in some of the peaks owing to the fact that theexperimental XRPD pattern was collected at room temperature and thecalculated XRPD pattern is derived from data collected at 100 K. Thereare also small intensity differences owing to preferred orientationeffects, present in the experimental pattern.

TABLE 2 Molecular formula C₂₄H₂₃N₃O₆ Molecular weight 449.45 CrystalSystem Monoclinic Space Group P21/n Unit Cell Dimensions a = 5.1305(4) Åb = 19.3861(15) Å c = 21.976(2)Å α = 90.00° β = 90.320(9)° γ = 90.00°Cell Volume 2185.7(3) Å³ Z  4 Temperature 100(1) K RadiationWavelength/type 1.54178 Å/CuKα Goodness of fit  1.008 R factor  0.0584Morphology Colourless needle

1.4 DSC of the 1:1 Tranilast Nicotinamide Cocrystal

The differential scanning calorimetry (DSC) trace, FIG. 4, shows asingle endotherm with an onset temperature of 168.1° C. and a peakmaximum of 175.4° C. corresponding to the melt of the cocrystal.

1.5 TGA of the 1:1 Tranilast Nicotinamide Cocrystal

The thermal gravimetric analysis (TGA) trace, FIG. 5, shows nosignificant weight loss prior to the cocrystal melt temperature with99.7% weight remaining at 170° C. The TGA shows that there is a weightloss of 27% between 170 and 253° C. This corresponds to one molarequivalent of nicotinamide.

1.6 ¹H NMR Spectrum of 1:1 Tranilast Nicotinamide Cocrystal

The ¹H NMR spectrum of the 1:1 tranilast nicotinamide cocrystal, shownin FIG. 6, displays the following peaks: ¹H NMR (400 MHz, d6-DMSO) δ:13.65 (1H), 11.31 (1H), 9.04 (1H), 8.71 (1H) 8.64 (1H), 8.22 (2H), 8.02(2H), 7.48-7.66 (4H), 7.40 (1H), 7.26 (1H), 7.18 (1H), 7.01 (1H), 6.81(1H), 3.84 (3H) and 3.81 (3 H). The peak at 9.04 ppm in the ¹H NMRspectrum corresponds to one proton on the aromatic ring of nicotinamide.Comparison of the integration of this peak with that at 8.02 ppm, whichcorresponds to one of the aromatic protons of tranilast, indicates thatthe cocrystal has an API:coformer stoichiometry of 1.1.

1.7 Physical Stability Study of the 1:1 Tranilast Nicotinamide Cocrystal

A stability study was carried out to examine the physical stability ofthe 1:1 tranilast nicotinamide cocrystal with respect to dissociationinto its starting components over time under accelerated conditions.Approximately 1-2 mg of the 1:1 tranilast nicotinamide cocrystal wasplaced in seven clear glass vials. The glass vials were loosely sealedwith plastic screw caps so as to provide a barrier to solid transfer butto still allow moisture equilibration with the outer environment. Thevial head space above the sample was estimated to be >95% of the totalvial volume. All seven samples were then placed on a tray and storedwithin a stability cabinet set at 40° C./75% RH. The individual sampleswere removed from the cabinet at pre-determined time points as shown inTable 3 and examined by XRPD. At every time point examined the XRPDpattern obtained was characteristic of the 1:1 tranilast nicotinamidecocrystal with no evidence of either of the starting materials, or anynew peaks to indicate conversion to a different crystalline form. FIG. 7illustrates the XRPD patterns obtained at the time points 0, threemonths and six months. FIG. 7 is an overlay of the XRPD patterns of the1:1 tranilast nicotinamide cocrystal at those time points during a 6month accelerated stability study at 40° C./75% RH. It can be seen thatthere is no obvious change within the sample over the six month periodand that there is no evidence of dissociation into either of thestarting materials, or conversion into another crystalline form oftranilast, indicating that the 1:1 tranilast nicotinamide cocrystal isstable under these conditions.

TABLE 3 XRPD Time Point Characterization 0 cocrystal 1 week cocrystal 2week cocrystal 3 week cocrystal 1 month cocrystal 2 months cocrystal 3months cocrystal 6 months cocrystal

Example 2 1:1 Tranilast Saccharin Cocrystal

2.1 Preparation of a 1:1 Tranilast Saccharin Cocrystal

The batch of the 1:1 tranilast saccharin cocrystal used forcharacterisation was prepared as follows:

Tranilast (250 mg) and saccharin (140 mg) were weighed into a glassvial. Dichloromethane (2.0 ml) was added to the vial. The resultingyellow slurry was placed in a shaker and matured for 5 days (RT to 50°C. on an 8 hour cycle, heating to 50° C. for 4 hours and then cooling toRT for a further 4 hours). The product was then filtered under vacuumdried under ambient conditions overnight.

2.2 XRPD Characterisation of a 1:1 Tranilast Saccharin Cocrystal

The experimental XRPD pattern of the 1:1 tranilast saccharin cocrystalis shown in FIG. 8. Table 4 lists the angles, °2θ±0.2°2θ, and d-spacingof the peaks identified in the experimental XRPD pattern of FIG. 8. Theentire list of peaks, or a subset thereof, may be sufficient tocharacterize the cocrystal, as well as by an XRPD pattern substantiallysimilar to FIG. 8. For example, a 1:1 tranilast saccharin cocrystal ofthe invention may be characterised by a powder X-ray diffraction patternhaving at least three peaks selected from 5.6, 9.5, 14.6, 15.4, 16.2 and16.7 °2θ±0.2°2θ.

TABLE 4 Angle d value °2θ ± 0.2 °2θ Angstrom Intensity % 5.6 15.91 28.57.4 12.02 2.8 9.5 9.35 6.4 11.1 7.94 100.0 11.5 7.68 4.1 12.1 7.34 2.412.5 7.05 4.9 12.8 6.89 3.0 13.8 6.43 6.1 14.3 6.17 5.5 14.6 6.06 55.815.4 5.76 12.9 15.9 5.57 4.4 16.2 5.45 10.1 16.7 5.29 46.5 18.2 4.88 3.719.0 4.66 12.2 20.2 4.39 2.7 20.7 4.29 3.3 21.4 4.14 8.5 22.0 4.03 3.122.4 3.96 13.3 22.8 3.90 2.7 23.2 3.83 10.7 23.8 3.74 11.3 24.1 3.69 8.825.0 3.56 11.2 25.3 3.51 5.6 25.7 3.47 6.1 25.9 3.43 11.4 26.7 3.34 2.427.3 3.26 3.7 27.6 3.23 10.1 27.9 3.20 11.1 28.1 3.17 5.4 28.8 3.09 3.029.5 3.03 2.8 30.4 2.94 5.0 30.8 2.90 2.4 31.0 2.88 4.6 32.0 2.80 2.433.7 2.66 5.1

2.3 DSC of the 1:1 Tranilast Saccharin Cocrystal

The differential scanning calorimetry (DSC) trace, FIG. 9, shows asingle endotherm with an onset temperature of 169.7° C. and a peakmaximum of 183.1° C. corresponding to the melt of the cocrystal.

2.4 TGA of the 1:1 Tranilast Saccharin Cocrystal

The thermal gravimetric analysis (TGA) trace, FIG. 10, shows nosignificant weight loss prior to the cocrystal melt temperature with99.8% weight remaining at 180° C.

2.5 ¹H NMR Spectrum of the 1:1 Tranilast Saccharin Cocrystal

The ¹H NMR spectrum of the 1:1 tranilast saccharin cocrystal, shown inFIG. 11, displays the following peaks: ¹H NMR (400 MHz, d6-DMSO) δ:11.29 (1H), 8.64 (1H), 8.17 (1H), 7.90-8.03 (4H), 7.61 (2H), 7.40 (1H),7.26 (1H), 7.18 (1H), 7.01 (1H), 6.81 (1H), 3.84 (3H) and 3.81 (3 H).The peak at 8.17 ppm in the ¹H NMR spectrum corresponds to one proton onthe aromatic ring of saccharin. Comparison of the integration of thispeak with that at 8.64 ppm, which corresponds to one of the aromaticprotons of tranilast, indicates that the cocrystal has an API:coformerstoichiometry of 1:1.

Example 3 1:1 Tranilast Gentisic Acid Cocrystal

3.1 Preparation of a 1:1 Tranilast Gentisic Acid Cocrystal

The batch of the 1:1 tranilast gentisic acid cocrystal used forcharacterisation was prepared as follows:

Tranilast (100 mg) was placed in a glass vial, 1.5 ml of a saturatedsolution of gentisic acid in acetonitrile was added to the vial. Theresulting yellow slurry was placed in a shaker and matured for 5 days(RT to 50° C. on an 8 hour cycle, heating to 50° C. for 4 hours and thencooling to RT for a further 4 hours). The product was then filteredunder vacuum and dried under ambient conditions overnight.

3.2 XRPD Characterisation of a 1:1 Tranilast Gentisic Acid Cocrystal

The experimental XRPD pattern of the 1:1 tranilast gentisic acidcocrystal is shown in FIG. 12. Table 5 lists the angles, °2θ±0.2°2θ, andd-spacing of the peaks identified in the experimental XRPD pattern ofFIG. 12. The entire list of peaks, or a subset thereof, may besufficient to characterize the cocrystal, as well as by an XRPD patternsubstantially similar to FIG. 12. For example, 1:1 tranilast gentisicacid cocrystal of the invention may be characterised by a powder X-raydiffraction pattern having at least three peaks selected from 7.4, 10.5,12.2, 14.8, 15.7, and 26.4°2θ±0.2°2θ.

TABLE 5 Angle d value °2θ ± 0.2 °2θ Angstrom Intensity % 4.2 20.85 1.06.1 14.48 0.7 7.4 12.00 1.0 10.5 8.43 0.8 12.2 7.23 4.7 12.7 6.99 3.613.0 6.82 14.1 13.8 6.43 0.9 14.1 6.26 1.3 14.8 5.96 9.3 15.8 5.60 0.817.4 5.08 0.6 18.0 4.93 4.4 18.3 4.84 3.4 18.9 4.70 1.3 20.2 4.38 0.722.3 3.98 1.8 23.0 3.86 3.9 23.7 3.75 1.2 24.6 3.61 100.0 25.0 3.56 2.225.2 3.53 0.9 25.5 3.48 0.7 26.2 3.40 2.8 26.4 3.37 7.2 26.8 3.32 1.927.2 3.28 0.7 28.1 3.17 1.7 29.2 3.05 0.7 32.0 2.80 0.7 32.4 2.76 0.634.9 2.57 0.6 36.5 2.46 1.1 37.3 2.41 1.2 37.9 2.37 0.6 38.2 2.35 0.739.4 2.28 0.6 39.7 2.27 0.7

3.3 DSC of the 1:1 Tranilast Gentisic Acid Cocrystal

The differential scanning calorimetry (DSC) trace, FIG. 13, shows asingle endotherm with an onset temperature of 170.6° C. and a peakmaximum of 182.1° C. corresponding to the melt of the cocrystal.

3.4 TGA of the 1:1 Tranilast Gentisic Acid Cocrystal

The thermal gravimetric analysis (TGA) trace, FIG. 14, shows nosignificant weight loss prior to the cocrystal melt temperature with99.7% weight remaining at 182° C.

3.5 ¹H NMR Spectrum of the 1:1 Tranilast Gentisic Acid Cocrystal

The ¹H NMR spectrum of the 1:1 tranilast gentisic acid cocrystal, shownin FIG. 15, displays the following peaks: ¹H NMR (400 MHz, d6-DMSO) δ:11.30 (1H), 8.65 (1H), 8.02 (1H), 7.55-7.66 (2H), 7.40 (1H), 7.26 (1H),7.15-7.21 (2H), 6.94-7.02 (2H), 6.77-6.84 (2H), 3.84 (3H) and 3.81 (3H). The multiplet between 6.94 and 7.02 ppm which integrates for 2protons, corresponds to one of the aromatic protons of tranilast and oneof the aromatic protons of gentisic acid. This indicates that thecocrystal has an API:coformer stoichiometry of 1:1.

Example 4 1:1 Tranilast Salicylic Acid Cocrystal

4.1 Preparation of a 1:1 Tranilast Gentisic Acid Cocrystal

The batch of the 1:1 tranilast salicyclic acid cocrystal used forcharacterisation was prepared as follows:

Tranilast (250 mg) and salicylic acid (104 mg) were weighed into a glassvial. Dichloromethane (2.0 ml) was added to the vial. The resultingyellow slurry was placed in a shaker and matured for 5 days (RT to 50°C. on an 8 hour cycle, heating to 50° C. for 4 hours and then cooling toRT for a further 4 hours). The product was then filtered under vacuumdried under ambient conditions overnight.

4.2 XRPD Characterisation of a 1:1 Tranilast Salicylic Acid Cocrystal

The experimental XRPD pattern of the 1:1 tranilast salicylic acidcocrystal is shown in FIG. 16. Table 6 lists the angles, °2θ±0.2°2θ, andd-spacing of the peaks identified in the experimental XRPD pattern ofFIG. 15. The entire list of peaks, or a subset thereof, may besufficient to characterize the cocrystal, as well as by an XRPD patternsubstantially similar to FIG. 16. For example, a 1:1 tranilast salicylicacid cocrystal of the invention may be characterised by a powder X-raydiffraction pattern having at least three peaks selected from 4.4, 10.4,13.1, 16.9 and 18.5 °2θ±0.2°2θ.

TABLE 6 Angle d value °2θ ± 0.2 °2θ Angstrom Intensity % 4.4 20.24 18.78.4 10.53 21.1 8.7 10.10 12.7 10.4 8.47 29.8 13.1 6.77 100.0 13.6 6.519.8 16.9 5.24 37.0 17.3 5.12 10.3 17.8 4.98 5.9 18.5 4.80 28.8 21.0 4.234.8 21.3 4.17 11.7 21.9 4.05 5.6 23.4 3.80 3.4 23.9 3.72 3.7 24.3 3.6614.8 24.6 3.62 4.7 25.4 3.50 30.8 26.4 3.38 12.5 27.3 3.26 3.5 28.0 3.1917.0 29.1 3.06 6.8 30.9 2.90 10.9 35.0 2.56 3.4 41.8 2.16 4.1

4.3 DSC of the 1:1 Tranilast Salicylic Acid Cocrystal

The differential scanning calorimetry (DSC) trace, FIG. 17, shows asingle endotherm with an onset temperature of 170.6° C. and a peakmaximum of 177.7° C.

4.4 TGA of the 1:1 Tranilast Salicylic Acid Cocrystal

The thermal gravimetric analysis (TGA) trace is shown in FIG. 18. It canbe seen that the cocrystal begins to lose weight at 141° C.

4.5 ¹H NMR Spectrum of the 1:1 Tranilast Salicylic Acid Cocrystal

The ¹H NMR spectrum of the 1:1 tranilast salicylic acid cocrystal, shownin FIG. 19, displays the following peaks: ¹H NMR (400 MHz, d6-DMSO) δ:11.30 (1H), 8.64 (1H), 8.02 (1H), 7.80 (1H), 7.49-7.66 (3H), 7.40 (1H),7.26 (1H), 7.18 (1H), 6.90-7.02 (3H), 6.82 (1H), 3.84 (3H) and 3.81(3H). The peak at 7.80 ppm in the ¹H NMR spectrum corresponds to oneproton on the aromatic ring of salicylic acid. Comparison of theintegration of this peak with that at 8.64 ppm, which corresponds to oneof the aromatic protons of tranilast, indicates that the cocrystal hasan API:coformer stoichiometry of 1:1.

Example 5 1:1 Tranilast Urea Cocrystal

5.1 Preparation of a 1:1 Tranilast Urea Cocrystal

The batch of the 1:1 tranilast urea cocrystal used for characterisationwas prepared as follows:

Tranilast (100 mg) and urea (18.3 mg) were placed in were placed in astainless steel ball mill. Isopropyl acetate (2 drops) was added. Thetwo components were ground together for 60 minute at 20 Hz. The productwas removed from the mill and the resulting colourless powder was leftto dry under ambient temperatures overnight.

5.2 XRPD Characterisation of a 1:1 Tranilast Urea Cocrystal

The experimental XRPD pattern of the 1:1 tranilast gentisic acidcocrystal is shown in FIG. 20. Table 7 lists the angles, °2θ±0.2°2θ, andd-spacing of the peaks identified in the experimental XRPD pattern ofFIG. 20. The entire list of peaks, or a subset thereof, may besufficient to characterize the cocrystal, as well as by an XRPD patternsubstantially similar to FIG. 20. For example, a 1:1 tranilast ureacocrystal of the invention may be characterised by a powder X-raydiffraction pattern having at least three peaks selected from 8.2, 11.3,13.8, 15.0, 16.3 and 25.3 °2θ±0.2°2θ.

TABLE 7 Angle d value °2θ ± 0.2 °2θ Angstrom Intensity % 8.2 10.76 10.811.3 7.81 38.2 12.6 7.00 33.0 12.8 6.93 37.2 13.2 6.71 100.0 13.8 6.4227.2 15.0 5.91 6.3 16.3 5.43 49.5 17.7 5.00 5.8 18.2 4.86 9.9 18.7 4.7317.0 21.1 4.21 26.7 21.4 4.14 23.2 22.3 3.99 28.7 22.5 3.94 45.1 23.13.84 27.5 23.5 3.79 9.1 23.8 3.73 6.1 24.7 3.60 19.1 25.3 3.51 86.6 26.43.37 6.1 27.7 3.22 10.8 28.2 3.17 59.8 28.8 3.10 21.0 30.5 2.93 9.0 33.02.72 11.5 34.4 2.61 9.1 38.0 2.37 9.2

5.3 DSC of the 1:1 Tranilast Urea Cocrystal

The differential scanning calorimetry (DSC) trace, FIG. 21, shows asharp endotherm with an onset temperature of 176.5° C. and a peakmaximum of 193.9° C. followed by a broad endothermic event between 202and 254° C.

5.4 TGA of the 1:1 Tranilast Urea Cocrystal

The thermal gravimetric analysis (TGA) trace, FIG. 22, shows nosignificant weight loss prior to 176.5° C., with 99.5% weight remainingat this temperature. The TGA shows that there is a weight loss of 15.5%between 177 and 223° C. This corresponds to one molar equivalent ofurea.

5.5 ¹H NMR Spectrum of the 1:1 Tranilast Urea Cocrystal

The ¹H NMR spectrum of the 1:1 tranilast urea cocrystal, shown in FIG.23, displays the following peaks: ¹H NMR (400 MHz, d6-DMSO) δ: 13.64(1H), 11.32 (1H), 8.64 (1H), 8.02 (1H), 7.55-7.66 (2H), 7.40 (1H), 7.27(1H), 7.17 (1H), 7.01 (1H), 6.82 (1H), 5.84 (4H), 3.84 (3H) and 3.81(3H). The peak at 5.84 ppm in the ¹H NMR spectrum corresponds to thefour protons of urea. Comparison of the integration of this peak withthat at 8.64 ppm, which corresponds to one of the aromatic protons oftranilast, indicates that the cocrystal has an API:coformerstoichiometry of 1:1.

Example 6 1:1 Tranilast 4-Aminobenzoic Acid Cocrystal

6.1 Preparation of a 1:1 Tranilast 4-Aminobenzoic Acid Cocrystal

The batch of the 1:1 tranilast 4-aminobenzoic acid cocrystal used forcharacterisation was prepared as follows:

Tranilast (300 mg) and was weighed into a glass vial. 3 ml of asaturated solution of 4-aminobenzoic acid in isopropylacetate was addedto the vial. The resulting yellow slurry was placed in a shaker andmatured for days (RT to 50° C. on an 8 hour cycle, heating to 50° C. for4 hours and then cooling to RT for a further 4 hours). The product wasthen filtered under vacuum and the resulting colourless crystals weredried under ambient conditions overnight.

6.2 XRPD Characterisation of a 1:1 Tranilast 4-Aminobenzoic AcidCocrystal

The experimental XRPD pattern of the 1:1 tranilast 4-aminobenzoic acidcocrystal is shown in FIG. 24. Table 8 lists the angles, °2θ±0.2°θ, andd-spacing of the peaks identified in the experimental XRPD pattern ofFIG. 24. The entire list of peaks, or a subset thereof, may besufficient to characterize the cocrystal, as well as by an XRPD patternsubstantially similar to FIG. 24. For example, a 1:1 tranilast4-aminobenzoic acid cocrystal of the invention may be characterised by apowder X-ray diffraction pattern having at least three peaks selectedfrom 5.4, 6.7, 11.5, 12.0, 16.4 and 17.9 °2θ±0.2θ.

TABLE 8 Angle d value °2θ ± 0.2 °2θ Angstrom Intensity % 5.4 16.21 14.86.7 13.23 12.9 9.3 9.51 6.7 10.6 8.34 10.5 11.5 7.71 87.3 12.0 7.37 37.714.0 6.30 13.9 14.7 6.02 16.9 15.4 5.77 88.4 16.4 5.41 100.0 17.1 5.1910.4 17.9 4.96 41.2 18.7 4.75 6.3 20.2 4.39 7.3 20.4 4.35 13.1 20.8 4.2724.6 21.9 4.05 18.7 22.4 3.96 5.4 22.9 3.87 6.9 23.6 3.76 10.3 24.2 3.688.9 24.5 3.64 13.9 25.2 3.54 5.4 25.7 3.46 10.4 26.2 3.40 9.3 27.1 3.2817.9 27.6 3.23 8.3 29.5 3.03 22.6 29.9 2.99 5.0 31.0 2.88 4.4 31.3 2.865.8 33.1 2.70 4.5 36.2 2.48 4.8 36.5 2.46 5.3 40.6 2.22 5.8

6.3 DSC of the 1:1 Tranilast 4-Aminobenzoic Acid Cocrystal

The differential scanning calorimetry (DSC) trace, FIG. 25, shows asharp endotherm with a peak maximum of 194.1° C. corresponding to themelt of the cocrystal.

6.4 TGA of the 1:1 Tranilast 4-Aminobenzoic Acid Cocrystal

The thermal gravimetric analysis (TGA) trace, FIG. 26, shows nosignificant weight loss prior to the cocrystal melt temperature, with99.5% weight remaining at 190° C.

6.5 ¹H NMR Spectrum of the 1:1 Tranilast 4-Aminobenzoic Cocrystal

The ¹H NMR spectrum of the 1:1 tranilast 4-aminobenzoic acid cocrystal,shown in FIG. 27, displays the following peaks: ¹H NMR (400 MHz,d6-DMSO) δ: 11.31 (1H), 8.64 (1H), 8.02 (1H), 7.55-7.66 (4H), 7.40 (1H),7.26 (1H), 7.14 (1H), 7.01 (1H), 6.82 (1H), 6.54 (2H), 3.84 (3H) and3.81 (3H). The peak at 6.54 ppm in the ¹H NMR spectrum corresponds tothe two protons on the aromatic ring of 4-aminobenzoic acid. Comparisonof the integration of this peak with that at 8.64 ppm, which correspondsto one of the aromatic protons of tranilast, indicates that thecocrystal has an API:coformer stoichiometry of 1:1.

Example 7 1:1 Tranilast 2,4-Dihydroxybenzoic Acid Cocrystal

7.1 Preparation of a 1:1 Tranilast 2,4-Dihydroxybenzoic Acid Cocrystal

Tranilast (100 mg) was weighed into a glass vial. 3 ml of a saturatedsolution of 2,4-dihydroxybenzoic acid in acetonitrile was added to thevial and the vial sealed. The resulting yellow slurry was placed in ashaker and matured for 5 days (RT to 50° C. on an 8 hour cycle, heatingto 50° C. for 4 hours and then cooling to RT for a further 4 hours). Theproduct was then filtered under vacuum and the resulting colourlesscrystals were dried under ambient conditions overnight.

7.2 XRPD Characterisation of a 1:1 Tranilast 2,4-Dihydroxybenzoic AcidCocrystal

The experimental XRPD pattern of the 1:1 tranilast 2,4-dihydroxybenzoicacid cocrystal is shown in FIG. 28. Table 9 lists the angles,°2θ±0.2°2θ, and d-spacing of the peaks identified in the experimentalXRPD pattern of FIG. 28. The entire list of peaks, or a subset thereof,may be sufficient to characterize the cocrystal, as well as by an XRPDpattern substantially similar to FIG. 28. For example, a 1:1 tranilast2,4-dihydroxybenzoic acid cocrystal of the invention may becharacterised by a powder X-ray diffraction pattern having at leastthree peaks selected from 3.9, 7.9, 11.8, 12.6 and 15.4 °2θ±0.2°2θ.

TABLE 9 Angle d value °2θ ± 0.2 °2θ Angstrom Intensity % 3.9 22.45 17.37.9 11.20 18.1 11.8 7.49 100.0 12.6 7.00 9.0 13.7 6.48 3.1 15.4 5.7385.4 16.8 5.29 6.8 17.3 5.12 3.6 19.0 4.67 4.6 21.4 4.15 2.8 22.6 3.922.7 23.3 3.82 10.5 23.7 3.74 6.4 25.4 3.50 6.2 26.5 3.36 4.7 27.1 3.294.2 27.7 3.21 4.0 28.4 3.14 3.9 28.8 3.10 3.3

7.3 DSC of the 1:1 Tranilast 2,4-Dihydroxybenzoic Acid Cocrystal

The differential scanning calorimetry (DSC) trace, FIG. 29, shows asharp endotherm with a peak maximum of 182.5° C. corresponding to themelt of the cocrystal.

7.4 TGA of the 1:1 Tranilast 2,4-Dihydroxybenzoic Acid Cocrystal

The thermal gravimetric analysis (TGA) trace, FIG. 30, shows nosignificant weight loss prior to the melt temperature of the cocrystalwith 99.5% weight remaining at 180° C. The TGA shows that there is aweight loss of 32% between 182 and 251° C. This corresponds to one molarequivalent of 2,4-dihydroxybenzoic acid.

7.5 ¹H NMR Spectrum of the 1:1 Tranilast 2,4-Dihydroxybenzoic Cocrystal

The ¹H NMR spectrum of the 1:1 tranilast 2,4-dihydroxybenzoic acidcocrystal, shown in FIG. 31, displays the following peaks: ¹H NMR (400MHz, d6-DMSO) δ: 13.53 (1H), 11.43 (1H), 11.30 (1H), 10.39 (1H), 8.63(1H), 8.02 (1H), 7.55-7.66 (3H), 7.40 (1H), 7.26 (1H), 7.18 (1H), 7.01(1H), 6.81 (1H), 6.34 (1H), 6.27 (1H), 3.84 (3H) and 3.81 (3H). The peakat 6.27 ppm in the ¹H NMR spectrum corresponds to one proton on thearomatic ring of 2,4-dihydroxybenzoic acid. Comparison of theintegration of this peak with that at 8.63 ppm, which corresponds to oneof the aromatic protons of tranilast, indicates that the cocrystal hasan API:coformer stoichiometry of 1:1.

Example 8 Solid-State Photostability Study

It is known that while pure crystalline tranilast is photostable in thesolid form, other solid forms of the API are not as photostable (S.Onoue. Eur J Pharm Sci. 2010; 39: 256-262). A study was, therefore,carried out to determine the solid-state photostability of the 1:1tranilast nicotinamide cocrystal, the 1:1 tranilast saccharin cocrystal,the 1:1 tranilast gentisic acid cocrystal, the 1:1 salicylic acidcocrystal, the 1:1 tranilast urea cocrystal, the 1:1 tranilast4-aminobenzoic acid cocrystal and the 1:1 tranilast 2,4-dihydroxybenzoicacid cocrystal and to compare this with the solid state photostabilityof pure crystalline tranilast. A 1-2 mg sample of crystalline tranilastand the seven cocrystal forms were each weighed and spread over thebottom surface of a clear glass vial. The vials were placed into aVindon Scientific Photostability cabinet and irradiated with UV light(average Klux=18.2 (18.2 Lux/hour), average UV values=2.55 watts/minute,temperature=31.0-32.0° C.). The percentage of tranilast remaining ineach sample, that had not undergone degradation into the cis-isomer,dimer or any other degradation product, was determined at 3, 24 and 48hours using HPLC. The HPLC method used is described in Table 10.

TABLE 10 Mobile Phase A 0.1% formic acid in purified water Mobile PhaseB 0.1% formic acid in methanol Column Zorbax Eclipse XDB-C18 50 × 4.6mm, 1.8 μm PS Column Temperature 35° C. Flow Rate 1.0 ml/min InjectionVolume 5 μl Wavelength 340 nm Run time 3 minutes Time (min) % A % BGradient Program 0 80 20 4  5 95 8  5 95 8.1 80 20

The results of this study are shown in Table 11. It can be seen fromTable 11 that in the solid-state the cocrystals are all photostableunder these conditions, with no indication of any photodegradation. Thestudy suggests that the 1:1 tranilast nicotinamide cocrystal, the 1:1tranilast saccharin cocrystal, the 1:1 tranilast gentisic acidcocrystal, the 1:1 salicylic acid cocrystal, the 1:1 tranilast ureacocrystal, the 1:1 tranilast 4-aminobenzoic acid cocrystal and the 1:1tranilast 2,4-dihydroxybenzoic acid cocrystal all have comparablephotostability in the solid-state to that of pure crystalline tranilast.

TABLE 11 Time 3 hrs 24 hrs 48 hrs Crystalline Tranilast 98.9% 99.8%99.7% 1:1 Tranilast Nicotinamide 99.3% 99.9% 99.9% Cocrystal 1:1Tranilast 4-Aminobenzoic Acid 99.8% 98.2% 99.7% Cocrystal 1:1 Tranilast2,4-Dihydroxybenzoic 99.9% 99.7% 99.8% Acid Cocrystal 1:1 TranilastGentisic Acid Cocrystal 99.6% 99.8% 99.9% 1:1 Tranilast SaccharinCocrystal 99.8% 99.6% 99.1% 1:1 Tranilast Urea Cocrystal 99.8% 99.6%99.9% 1:1 Tranilast Salicyclic Acid 99.8% 99.6% 98.7% Cocrystal

Example 9 Solution Photostability Study

Crystalline tranilast is photochemically unstable once dissolved insolution, transforming into cis-isomer and dimer forms upon UV exposure(N. Hori. Chem Pharm Bull. 1999; 47: 1713-1716). This study explored thephotostability of the 1:1 tranilast nicotinamide cocrystal, the 1:1tranilast saccharin cocrystal, the 1:1 tranilast gentisic acidcocrystal, the 1:1 salicylic acid cocrystal, the 1:1 tranilast ureacocrystal, the 1:1 tranilast 4-aminobenzoic acid cocrystal and the 1:1tranilast 2,4-dihydroxybenzoic acid cocrystal once dissolved in solutionand to compare these with the solution photostability of pure tranilast.A 1 mg sample of crystalline tranilast and the seven cocrystal formswere each weighed into a clear glass vial. Each sample was dissolved ina mixture of DMSO (200 μl), MeOH (600 μl) and water (600 μl). The vialswere placed into a Vindon Scientific Photostability cabinet andirradiated with UV light (average Klux=18.2 (18.2 Lux/hour), average UVvalues=2.55 watts/minute, temperature=31.0-32.0° C.). The percentage oftranilast remaining in each sample, that had not undergone degradationinto the cis-isomer, dimer or any other degradation product, wasdetermined after 24 hours using HPLC. The HPLC method used is describedin Table 10. The results of this study are shown in Table 12.

TABLE 12 Time Composition 24 hrs Crystalline Tranilast 66.2% 1:1Tranilast Nicotinamide 80.2% Cocrystal 1:1 Tranilast 4- 76.2%Aminobenzoic Acid Cocrystal 1:1 Tranilast 2,4- 79.1% DihydroxybenzoicAcid Cocrystal 1:1 Tranilast Gentisic Acid 76.3% Cocrystal 1:1 TranilastSaccharin 71.0% Cocrystal 1:1 Tranilast Urea Cocrystal 76.4% 1:1Tranilast Salicyclic Acid 77.5% Cocrystal

It can be seen from Table 12 that the cocrystal forms of tranilast havehigher photostability in solution after 24 hours compared with purecrystalline tranilast.

Example 10 Dissolution Study

For poorly soluble drugs, such as tranilast, the rate of dissolution ofthe drug form used can have an impact on the overall absorption and thusbioavailability of the drug, especially for example, in the case of oralsolid dosage or inhalation delivery methods. A study was, therefore,carried out to examine the rate of dissolution of the 1:1 tranilastnicotinamide cocrystal, the 1:1 tranilast saccharin cocrystal, the 1:1tranilast gentisic add cocrystal, the 1:1 salicylic acid cocrystal, the1:1 tranilast urea cocrystal, the 1:1 tranilast 4-aminobenzoic acidcocrystal and the 1:1 tranilast 2,4-dihydroxybenzoic acid cocrystalcompared with that of pure crystalline tranilast. The dissolutionexperiment was carried out for tranilast and each of the cocrystal formsat a concentration equivalent to 0.4 mg tranilast/ml in purified watercontaining 2% SDS. This study compared the dissolution rates of thecocrystals versus pure crystalline tranilast, because of the extremelylow solubility of crystalline tranilast in aqueous media, the surfactantsodium dodecyl sulfate (SDS) was added to the dissolution media to alloweasier analytical detection. Samples were collected and analyzed at 1,5, 10 and 30 minute time points. The samples were analyzed by HPLC usingthe method described in Table 10. FIG. 32 illustrates the dissolutionprofiles from a single dataset for each of the tranilast cocrystalsalongside crystalline tranilast over the 30 minute time period in theaqueous 2% SDS solution. The dissolution data is corrected within errorlimits of the analytical method described (estimated at ±10%). It can beseen from this graph that all of the cocrystals demonstrate accelerateddissolution behaviour in this media compared to crystalline tranilast.Most of the cocrystals reach almost their maximum dissolution within thefirst minute. In particular the 1:1 tranilast nicotinamide cocrystalshows almost complete dissolution within 1 minute whereas thecrystalline tranilast is only about 5% dissolved after this time. It canbe seen that all of the cocrystals have different dissolution rates inthis media demonstrating how different cocrystals can impart differentproperties to tranilast and that the exact properties of a cocrystal cannot be predicted simply from the properties of the coformer used.

The claimed invention is:
 1. A 1:1 tranilast nicotinamide cocrystal,wherein the cocrystal is characterised by at least one of: a powderX-ray diffraction pattern having at least three peaks selected from 6.0,8.0, 12.0, 15.0 and 15.6 °2θ±0.2°2θ; or a powder X-ray diffractionpattern substantially similar to FIG.
 1. 2. A pharmaceutical compositioncomprising a tranilast cocrystal of claim 1 and a pharmaceuticallyacceptable carrier.
 3. A pharmaceutical composition of claim 2, whereinthe composition is a topical formulation.
 4. A pharmaceuticalcomposition of claim 2, wherein the composition is an inhalableformulation.
 5. A method of preparing a liquid pharmaceuticalcomposition comprising the step of dissolving a tranilast cocrystal ofclaim 1 in a pharmaceutically acceptable solvent.
 6. A pharmaceuticalcomposition of claim 2, wherein the composition is an oral formulation.7. A pharmaceutical composition of a tranilast cocrystal of claim 1prepared by dissolving the tranilast cocrystal in a pharmaceuticallyacceptable solvent.
 8. A pharmaceutical composition of claim 7, whereinthe pharmaceutical composition is an injectable formulation.